14-membered ketolides and methods of their preparation and use

Abstract

Provided herein are methods of preparing new 14-membered ketolides via coupling of an eastern and western half moiety, followed by macrocyclization, and optional functionalization. Intermediates in the synthesis of these ketolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using these ketolides are also provided.

What is claimed is: 
     
       1. A method of treating an infectious disease or an inflammatory condition comprising administering an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 Z is of the formula 
 
       
       
         
           
           
               
               
           
         
         
           each instance of R 1a , R 1b , R 2a , and R 2b  is independently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl, or wherein R 1a  and R 1b  or R 2a  and R 2b  are taken together to form 
         
       
       
         
           
           
               
               
           
         
         
           a indicates the point of attachment to the carbon substituted by —NR 14 —; 
           b indicates the point of attachment to L 3 ; 
           each of R o1  and R o2  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl; 
           R sa  is hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl; 
           L 3  is a group of formula: 
         
       
       
         
           
           
               
               
           
         
         
             represents a single or double bond; 
           R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , or an oxygen protecting group 
           R 4  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
           each instance of R 18  and R 19  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
           each instance of R 20  and R 21  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, halogen, or carbonyl, or R 20  and R 21  are joined to form an optionally substituted cyclopropyl or an oxiranyl ring; 
           each instance of R 5a  and R 5b  is independently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; 
           R 6  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, or halogen; 
           R 7  and R 8  are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
           R 9  and R 17  are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , an oxygen protecting group, or a carbohydrate; 
           R 10  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, or halogen; 
           G 3  is —O—, —S—, or —N(R G1 )—, wherein R G1  is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; 
           R 14  is a group of formula: 
         
       
       
         
           
           
               
               
           
         
         
           L C1  is a linking group selected from the group consisting of optionally substituted alkenylene, optionally substituted alkynylene, and optionally substituted carbocyclylene; 
           L C2  is a bond;
 A is optionally substituted carbocyclene, optionally substituted imidazolene, optionally substituted tetrazolene, 
 
         
       
       
         
           
           
               
               
           
         
         
           R W2  is hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; optionally substituted heterocyclyl; optionally substituted aryl; or optionally substituted heteroaryl; 
           R 23  is optionally substituted aryl; or optionally substituted heteroaryl; and 
           each instance of R Z8  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R Z8  groups are joined to form an optionally substituted heterocylyl or optionally substituted heteroaryl ring; 
         
         to a subject in need thereof. 
       
     
     
       2. The method of  claim 1 , wherein the compound is of Formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. The method of  claim 1 , wherein L 3  is a group of formula: 
       
         
           
           
               
               
           
         
       
     
     
       4. The method of  claim 1 , wherein R 4  is hydrogen, optionally substituted C 1-6  alkyl, or optionally substituted C 2-6  alkenyl. 
     
     
       5. The method of  claim 1 , wherein R 9  is a group of formula: 
       
         
           
           
               
               
           
         
         wherein:
 each of R S1 , R S2a , R S2b , R S3a , R S3b , R S4a , R S4b , R S5a , and R S5b  is independently hydrogen, optionally substituted alkyl, —OR SO , or —N(R SN ) 2 , or wherein R S2a  or R S2b  may be taken together with R S3a  or R S3b  to form an optionally substituted fused heterocyclic ring; 
 each instance of R SO  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group; and 
 each instance of R SN  is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; or optionally two R SN  are taken with the intervening atoms to form a heterocyclic ring. 
 
       
     
     
       6. The method of  claim 1 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
       7. The method of  claim 1 , wherein R 23  is of formula: 
       
         
           
           
               
               
           
         
         wherein:
 each instance of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , and V 9  may independently be O, S, N, NR 23N , C, or CR 23C , as valency permits; 
 R 23N  is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or a nitrogen protecting group; and 
 R 23C  is hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, or carbonyl. 
 
       
     
     
       8. The method of  claim 7 , wherein R 23  is of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein x is 0, 1, or 2. 
       
     
     
       9. The method of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
       10. The method of  claim 1 , wherein the infectious disease is a bacterial infection. 
     
     
       11. The method of  claim 10 , wherein the bacterial infection is an infection with a Gram positive bacteria. 
     
     
       12. The method of  claim 10 , wherein the bacterial infection is an infection with a Gram negative bacteria. 
     
     
       13. The method of  claim 10 , wherein the bacterial infection is a  Staphylococcus  infection, a  Bacillus  infection, a  Streptococcus  infection, an  Escherichia  infection, or a  Haemophilus  infection. 
     
     
       14. The method of  claim 10 , wherein the infectious disease is a parasitic infection. 
     
     
       15. The method of  claim 1 , wherein each of L C1  is 
       
         
           
           
               
               
           
         
         wherein each instance of p is 0, 1, or 2. 
       
     
     
       16. The method of  claim 1 , wherein L C1  is 
       
         
           
           
               
               
           
         
       
     
     
       17. The method of  claim 1 , wherein R 6  is —CH 3 ; and R 10  is fluorine. 
     
     
       18. The method of  claim 1 , wherein R 7  is —CH 2 CH 3 ; and R 8  is —CH 3 . 
     
     
       19. The method of  claim 1 , wherein R 9  is a group of formula: 
       
         
           
           
               
               
           
         
       
     
     
       20. The method of  claim 1 , wherein the inflammatory condition is a chronic pulmonary inflammatory syndrome. 
     
     
       21. The method of  claim 1 , wherein the method is treating an infectious disease. 
     
     
       22. The method of  claim 1 , wherein the method is treating an inflammatory condition.